RGA6201 PROJECT #1 – GROUP #2

THE REGULATORY JOURNEY OF CHANTIX

Members

•Hal Neville-Jones•Irina Fedorov•Sunder Singh Bob Gottumukkala •Manasa Survi•Devang Baraot•Phani Venkata Sekhar Puppala•Reema Bhatt•Shruti Nayak

Introduction:

Which drug we chose and why:

Drug: VarenclineBrand name: ChantixSponsor: PfizerIndication: Smoking cessation.

Why is this drug of Particular interest?

•Smoking related illness cause 440,000 deaths annually and is the second largest cause of preventable deaths in the United States .

•57.4 million people in the U.S. who smoke of which 52.4% want to quit.•Chantix is a non-nicotine treatment with only one current competitor in the market, known as Zyban.

Description of Chantix:

•Active ingredient: Varenicline (as tartrate salt), which is a partial agonist selective for α4β2

nicotinic acetylcholine receptor subtypes.

•Molecular weight: 361.35 Daltons•Molecular formula: C13H13N3 •C4H6O6

How it works?

•There are receptors for nicotine in your brain.

•When you smoke, the nicotine you inhale binds to these receptors.•These receptors sends message to different parts of your brain to release a chemical called dopamine.

•Dopamine gives feeling of pleasure. But it does not last long. That's why your body craves for more nicotine. This can become a vicious cycle.

Chemical Structure

Continued…

•Acting as a partial agonist varenicline binds to, and partially stimulates, the α4β2 receptor without producing a full effect like nicotine.

•Thus varenicline does not greatly increase the downstream release of dopamine.

Indication:

•Used as an aid in smoking cessation treatment.

General and Product specific FDA Guidance Documents

Chemistry Manufacturing and Controls:•CMC should meet certain factors as per the section 506 A (b) of the Federal FDC Act to obtain a safe and effective product.

•Chantix is manufactured by Conventional Chemical Synthesis.

•Post approval CMC changes must be reported to FDA as per section 506 A of the Federal FD&C Act.

Clinical Pharmacology and Toxicology:

•Mechanism of Action: Partial agonist, selective binder for α4 β2 nicotinic

acetylcholine receptors.

•Pharmacokinetics: High plasma concentration and 90% systemic bioavailability can be achieved within 4 days.

Continued….

Labeling:•Chantix is an Nicotine Replacement Therapy (NRT) Product.

•FDA prescribed the labeling for Chantix through Drug Safety Communication Program.

Advertising:•Direct To Consumer (DTC) advertising under FDAAA DTC Television Ad Pre-Dissemination Review Program.

•FDA plans to advertise in the form of DTC under the section 503 B of the Food, Drug and Cosmetic Act (the FD&C Act).

Drug Safety:•Chantix is a prescription drug, indicated in patients with cardiac or blood vessel problems, Chronic Obstructive Pulmonary Disease (COPD).

•Common side effects are mood alterations, hostility and suicidal thoughts.

A Summary of Pre-Clinical Safety Data of Chantix submitted by Pfizer Inc., in their IND and NDA

Varinicline , the main constituent and active ingredient of Chantix was used in the pre-clinical studies.1.Carcinogenicity: •In mice, no evidence of carcinogenicity even at 47 times (20 mg/kg/day) higher than the human dose.

•In male rats, hibernoma was observed. One tumor at 5 mg/kg/day and 2 benign tumors at 15 mg/kg/day. (negligible to human dose)

•No occurrences of hibernoma in female rats at any dose.

2.Mutagenesis: •Varenicline was found negative for Ames test, in-vitro cytogenetic tests and gene mutation assays performed on human and mammalian cells - reveals no potential for mutation and genotoxicity.

3.Infertility in females: • No infertility observed in male and female rats at dosage of 5mg/kg/day.• But decreased offspring number in pregnant rats at 15 mg/kg/day administered orally.

Continued…4. Pregnancy: •Found not teratogenic in animals even at doses 36 and 72 times greater than the recommended human dose.•There were some non-teratogenic effects during animal reproduction studies showing reduced weight of the fetus.•Contraindicated in pregnancy.

5. Emesis: •Varenicline binds with 5 HT3 receptor, causing emesis. But ondasetron blocks the effect.

6. Local toxicology:•No Photo toxicity, Dermal toxicity, skin sensitization (as seen negative in guinea pigs)

7. Ocular toxicology: •Mild irritation at 10 times the human dose. Iris and conjuctival irritation in all treated rabbits. An acute effect of irritation in skin or eye is seen as the nicotine is deposited in the melanin tissue. This occurs only if there is a dermal or ocular contact with the drug.

Investigational New Drug Application• IND: The IND is a request for an exemption from the federal statute that prohibits an unapproved drug from being shipped in interstate commerce.

• FDA clears IND, never approves.

• Type of IND for Chantix : Commercial IND

• 10 Principles included in IND application: 1.Cover sheet2.Table of Contents3.Introductory statements4.General Investigational Plans5.Investigator’s Brochure6.Clinical Protocol7.Chemistry, Manufacturing and control data8.Pharmacological and Toxicological data9.Previous Human Experience10.Additional Information, like pediatrics information

Site of IND’s Cover sheet (Form 1571)http://www.fda.gov/downloads/aboutfda/reportsmanualsforms/forms/ucm083533.pdf

Pfizer’s Investigational Plan for Chantix

•6 Clinical trials and 3659 chronic smokers.

Study 1: •Dose ranging-Placebo controlled Phase II to investigate optimum treatment regimen of drug.

•Total dose: 1mg/2mg daily

Study 2: •Placebo controlled trial, 627 patients, 0.5/1 mg dose or Placebo twice daily for 12 weeks.

Study 3:•Placebo-controlled flexible dosing study, 312 subjects.

•To investigate the effects of a patient-directed dosing strategy.

•Initial regimen of 0.5 mg twice daily, followed by a patient-adjusted schedule of 0.5 mg once or twice daily (freely adjusted).

Continued….

Studies 4 & 5: •Identical, active- and placebo-controlled studies. •Would enroll 1022 (Study 4) and 1023 (Study 5) subjects, who would receive 1 mg Chantix twice daily, 150 mg of the approved smoking cessation aid bupropion sustained-release twice daily, or placebo, for 12 weeks, with subsequent 40 week observational follow-up.

Long-Term Follow-up:•Studies 1-5 all included 40 week follow-up periods, which would investigate long-term abstinence rates following a course of treatment.

Study 6: •This open label study would enroll 1927 chronic smokers, and was designed to investigate the efficacy of the drug on promoting long-term smoking abstinence.

Conclusion:

•As Chantix targets the neuropsychiatric part of the body, its side effects are expected to be little risky.•July 2009 FDA mandated a black box warning for the labeling.•But still FDA never recalled the product.•Varenicline received a "priority review" by the FDA in February 2006, shortening the usual 10-month review period to 6 months.•Prior studies and the post market studies suggest that Chantix is the only treatment option available to help people stop smoking.•Final decision up to the smoker whether to get rid of it or suffer the consequences.

THANK YOU

References:

•CDC. "Smoking & Tobacco Use." Centers for Disease Control and Prevention.http://www.cdc.gov/tobacco/data_statistics/fact_sheets/cessation/quitting/ (accessed October 1, 2013).

•Kuehn, BM. "FDA Speeds Smoking Cessation Drug Review." The Journal of the American Medical Association. http://jama.jamanetwork.com/article.aspx?articleid=202335 (accessed October 1, 2013).

•‘CFR - Code of Federal Regulations Title 21’, US Food and Drug Administration Home, Last Updated on: 04/01/2013.http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/investigationalnewdrugindapplication/default.htm

•‘Drug’, US Food and Drug Administration Home, Last Updated on: 04/25/2013http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/investigationalnewdrugindapplication/default.htm

•Submitting IND: what you need to know’, US Food and Drug Administration, SBA Educational forum; October 15, 2009 http://www.fda.gov/downloads/Drugs/NewsEvents/UCM185912.pdf

•FDA Approved Drugs: Chantix (Varnicline)’, CentreWatch;http://www.centerwatch.com/drug-information/fda-approvals/drug-details.aspx?DrugID=897